The present invention relates to compounds having the general
formula (I) with the definitions of A, X, R1-R4 given below,
and/or a salt or ester thereof.
Furthermore, the invention relates to the use of said compounds for the treatment
of Alzheimer's disease and their use for the modulation of &ggr;-secretase activity.

Alzheimer's Disease (AD) is a progressive neurodegenerative
disorder marked by loss of memory, cognition, and behavioral stability. AD afflicts
6-10% of the population over age 65 and up to 50% over age 85. It is the leading
cause of dementia and the third leading cause of death after cardiovascular disease
and cancer. There is currently no effective treatment for AD. The total net cost
related to AD in the U.S. exceeds $100 billion annually.

AD does not have a simple etiology, however, it has been
associated with certain risk factors including (1) age, (2) family history (3) and
head trauma; other factors include environmental toxins and low level of education.
Specific neuropathological lesions in the limbic and cerebral cortices include intracellular
neurofibrillary tangles consisting of hyperphosphorylated tau protein and the extracellular
deposition of fibrillar aggregates of amyloid beta peptides (amyloid plaques). The
major component of amyloid plaques are the amyloid beta (A-beta, Abeta or A&bgr;)
peptides of various lengths. A variant thereof, which is the A&bgr;1-42-peptide
(Abeta-42), is believed to be the major causative agent for amyloid formation. Another
variant is the A&bgr;1-40-peptide (Abeta-40). Amyloid beta is the proteolytic
product of a precursor protein, beta amyloid precursor protein (beta-APP or APP).

Familial, early onset autosomal dominant forms of AD have
been linked to missense mutations in the &bgr;-amyloid precursor protein (&bgr;-APP
or APP) and in the presenilin proteins 1 and 2. In some patients, late onset forms
of AD have been correlated with a specific allele of the apolipoprotein E (ApoE)
gene, and, more recently, the finding of a mutation in alpha2-macroglobulin, which
may be linked to at least 30% of the AD population. Despite this heterogeneity,
all forms of AD exhibit similar pathological findings. Genetic analysis has provided
the best clues for a logical therapeutic approach to AD. All mutations, found to
date, affect the quantitative or qualitative production of the amyloidogenic peptides
known as Abeta-peptides (A&bgr;), specifically A&bgr;42, and have given strong
support to the "amyloid cascade hypothesis" of AD (Tanzi and Bertram, 2005, Cell 120, 545). The likely link between A&bgr; peptide generation and AD pathology
emphasizes the need for a better understanding of the mechanisms of A&bgr; production
and strongly warrants a therapeutic approach at modulating A&bgr; levels.

The release of A&bgr; peptides is modulated by at least
two proteolytic activities referred to as &bgr;- and &ggr;- secretase cleaving
at the N-terminus (Met-Asp bond) and the C-terminus (residues 37-42) of the A&bgr;
peptide, respectively. In the secretory pathway, there is evidence that &bgr;-secretase
cleaves first, leading to the secretion of s-APP&bgr; (s&bgr;) and the retention
of a 11 kDa membrane-bound carboxy terminal fragment (CTF). The latter is believed
to give rise to A&bgr; peptides following cleavage by &ggr;-secretase. The amount
of the longer isoform, A&bgr;42, is selectively increased in patients carrying
certain mutations in a particular protein (presenilin), and these mutations have
been correlated with early-onset familial Alzheimer's disease. Therefore, A&bgr;42
is believed by many researchers to be the main culprit of the pathogenesis of Alzheimer's
disease.

It has now become clear that the &ggr;-secretase activity
cannot be ascribed to a single particular protein, but is in fact associated with
an assembly of different proteins.
The gamma-secretase activity resides within a multiprotein complex containing at
least four components: the presenilin (PS) heterodimer, nicastrin, aph-1 and pen-2.
The PS heterodimer consists of the amino- and carboxyterminal PS fragments generated
by endoproteolysis of the precursor protein. The two aspartates of the catalytic
site are at the interface of this heterodimer. It has recently been suggested that
nicastrin serves as a gamma-secretase-substrate receptor. The functions of the other
members of gamma-secretase are unknown, but they are all required for activity (Steiner, 2004. Curr. Alzheimer Research 1(3): 175-181).

Thus, although the molecular mechanism of the second cleavage-step
has remained elusive until present, the &ggr;-secretase-complex has become one
of the prime targets in the search for compounds for the treatment of Alzheimer's
disease.
Various strategies have been proposed for targeting gamma-secretase in Alzheimer's
disease, ranging from targeting the catalytic site directly, developing substrate-specific
inhibitors and modulators of gamma-secretase activity (Marjaux et al., 2004. Drug Discovery Today: Therapeutic Strategies, Volume
1, 1-6). Accordingly, a variety of compounds were described that have secretases
as targets (Lamer, 2004. Secretases as therapeutics targets in Alzheimer's disease: patents
2000 - 2004. Expert Opin. Ther. Patents 14, 1403-1420.)

Indeed, this finding was recently supported by biochemical
studies in which an effect of certain NSAIDs on &ggr;-secretase was shown (Weggen et al (2001) Nature 414, 6860, 212 and WO 01/78721 and US 2002/0128319; Morihara et al (2002) J. Neurochem. 83, 1009; Eriksen (2003) J. Clin. Invest. 112 , 440). Potential limitations for the use of NSAIDs to prevent or treat AD are
their inhibition activity of Cox enzymes, which can lead to unwanted side effects,
and their low CNS penetration (Peretto et al., 2005, J. Med. Chem. 48, 5705-5720).

Thus, there is a strong need for novel compounds which
modulate &ggr;-secretase activity thereby opening new avenues for the treatment
of Alzheimer's disease.

The object of the present invention is to provide such
compounds.

The object is achieved by a compound having the general
formula (I)
wherein
A is O, S or NH,
X is a bond or a group -CR5R6 wherein R5 and R6
are, independently of each other, selected from the group consisting ofH; alkyl
selected from the group CH3, C2H5, i-C3H7,
n-C3H7, i-C4H9, n-C4H9,
sec-C4H9, tert-C4H9; alkenyl selected
from C2H3, i-C3H5, n-C3H5,
n-C4H7, i-C4H7, sec-C4H7;
wherein in the all named alkyl and alkenyl groups one or more H atom is optionally
substituted with one or more substituents independently selected from the group
consisting ofF, Cl, Br, I and CF3; or R5 and R6
being part of a ring, either saturated or unsaturated, substituted or unsubstituted,
having 3 to 6 C-atoms, and which may contain in the ring one or more heteroatoms
from the group N, S or O, and which heteroatom may be identical or different if
more than one heteroatom is present;
R1, R2, R3 and R4 are independently
selected from the group consisting of H; F; Cl; Br; I; CN; OH; C(O)N(R7R8);
S(O)2R7; SO2N(R7R8); S(O)N(R7R8);
N(R7)S(O)2R8; N(R8)S(O)R8;
S(O)2R7; N(R7)S(O)2N(R8R8a);
SR7; N(R7R8); N(R7)C(O)R8;
N(R7)C(O)N(R8R8a); N(R7)C(O)OR8;
OC(O)N(R7R8); C(O)R7; substituted and unsubstituted
C1-C4-alkyl and substituted and unsubstituted C1-C4-alkoxy,
and wherein the substituents of both groups C1-C4-alkyl and
C1-C4-alkoxy are selected from F, Cl, Br, I, CF3;
R7, R8, R8a are independently selected from the
group consisting of H; C1-C4-alkyl; heterocyclyl; and C3-7
cycloalkyl, wherein C1-C4-alkyl; heterocyclyl; and C3-7
cycloalkyl are optionally substituted with one or more substituents independently
selected from the group consisting of F, C1, Br, I and CF3;
Y is a carboxy group -C(O)OH or a substituted or unsubstituted tetrazole group and/or
a salt or ester thereof

The term "substituted" as used herein includes both part
and full substitution. Substituents can be either saturated or unsaturated.

In case R5 and R6 are part of a ring, the ring can be substituted
by C1-C4-alkyl or F, Cl, Br, I and CF3

Esters are those according to formula (I) in which H of
the carboxy group is replaced by an organic residue R7a. Suitable organic
residues are known to a person skilled in the art. Preferred R7a include
the following:

An unsubstituted or at least monosubstituted alkyl, preferably
a C1-C10 alkyl, an alkenyl, preferably C2-C10-alkenyl,
an alkynyl, preferably C3-C10-alkynyl, and an unsubstituted
or at least monosubstituted, saturated or unsaturated, non-aromatic or aromatic
ring having 3 to 6 C-atoms, and which may contain in the ring one or more heteroatoms
from the group N, S or O, and which heteroatom may be identical or different if
more than one heteroatom is present. Said substituents being selected from the group
consisting of halogen, alkyl, alkenyl, alkynyl, N, S, O, carboxy, sulphonyl, and
the like and which can be further substituted.

Examples for current aromatic groups include aryl groups,
for example phenyl groups, and heteroaryl groups, which aryl and heteroaryl groups
may be substituted, preferably by the substituents given above.

The term "C1-C4-alkyl" refers to
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert.-butyl.

"Heterocyclyl" or "heterocycle" means a cyclopentane, cyclohexane
or cycloheptane ring that may contain up to the maximum number of double bonds (aromatic
or non-aromatic ring which is fully, partially or un-saturated) wherein at least
one carbon atom up to 4 carbon atoms are replaced by a heteroatom selected from
the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and
nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule
via a carbon or nitrogen atom. Examples for a heterocycle include but are not restricted
to furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline,
oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline,
thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine,
pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine,
sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine,
pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine,
tetrazolidine, azepine or homopiperazine. "Heterocycle" means also azetidine.

In preferred embodiments, the invention relates to a compound
having the general formula (I) wherein A, X; Y; R1 and R2;
and R3, R4, R5 and R6 independently
of each other have the following meanings:

A is O; and/or

X is a group -CR5R6 wherein R5 and R6
are, independently of each other, selected from the group consisting of H; alkyl
selected from the group CH3, C2H5, i-C3H7,
n-C3H7, i-C4H9, n-C4H9,
sec-C4H9, tert-C4H9; wherein in the
all named alkyl groups one or more H atom is optionally substituted with one or
more substituents independently selected from the group consisting of F, Cl, Br
and I; and/or

R1, R2, R3 and R4 are independently
selected from the group consisting of H; OH; C1-C4-alkyl or
C1-C4-alkoxy, substituted partly or fully by F, Cl, Br, I; and/or

R5 and R6 being H; or R5 being H and R6
being CH3, C2H5, C3H7 or
C4H9 or isomers thereof; or R1 and R2
being CH3 or R1, R2 jointly form together with
the carbon atom to which they are attached a cyclopropyl ring; and/or

Y is a carboxy group

and/or a salt or ester thereof

Within this group of embodiments, it is even more preferred
if all the groups A; X; Y; R1, R2, R3, R4,
R5 and R6 have the meanings defined beforehand.

It is even more preferred if A; X; Y; R1 and
R2; and R3, R4, R5 and R6
independently of each other have the following meanings:

A is O; X is a group -CR5R6 with R5 and R6
being H; or R5 being H and R6 being CH3, C2H5,
C3H7 or C4H9 or isomers thereof; or
R5 and R6 being CH3 or R5, R6
jointly form together with the carbon atom to which they are attached a cyclopropyl
ring; and/or

R1, R2, R3 and R4 are independently
selected from the group consisting of H; OH; C1-C4-alkyl or
C1-C4-alkoxy, substituted partly or fully by F, C1, Br, I; and/or

and/or

Y is a carboxy group

and/or a salt or ester thereof

Within this group of embodiments, it is even more preferred
if all the groups A; X; Y; R1, R2, R3, R4,
R5 and R6 have the meanings defined beforehand.

It is still more preferred if A; X; Y; R1 and
R2; and R3, R4, R5 and R6
independently of each other have the following meanings:

AisO;

X is a group -CR5R6 , with R5 and R6
being H; or R5 being H and R6 being CH3, C2H5,
C3H7 or C4H9 or isomers thereof;

Y is a carboxy group

R1, R2, R3 and R4 are independently
selected from the group consisting of H, OH, CH3, OCH3, CF3,
F, and Cl; and/or

and/or a salt or ester thereof

Within this group of embodiments, it is even more preferred
if all the groups A; X; Y; R1 and R2; and R3, R4,
R5 and R6 have the meanings defined beforehand.

In an even more preferred embodiment, the invention relates
to compounds selected from the group consisting of
2-(5-(4-fluorophenoxy)-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid (I)
2-(5-(phenoxy)-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid (II)

Some of the compounds of the inventions and/or salts or
esters thereof will exist in different stereoisomeric forms. All of these forms
are subjects of the invention.

Described below are exemplary salts of the compounds according
to the invention which are included herein. The list of the different salts stated
below is not meant to be complete and limiting.

Compounds according to the invention which contain one
or more acidic groups can be used according to the invention, e.g. as their alkali
metal salts, alkaline earth metal salts or ammonium salts. More precise examples
of such salts include sodium salts, potassium salts, calcium salts, magnesium salts
or salts with ammonia or organic amines such as, e.g. ethylamine, ethanolamine,
triethanolamine or amino acids.

Compounds according to the invention which contain one
or more basic groups, i.e. groups which can be protonated, can be used according
to the invention in the form of their addition salts with inorganic or organic acids.

The term "pharmaceutically acceptable" means approved by
a regulatory agency such as the EMEA (Europe) and/or the FDA (US) and/or any other
national regulatory agency for use in animals, preferably in humans.

Compounds according to the invention which contain several
basic groups can simultaneously form different salts.

If a compound according to the invention simultaneously
contains acidic and basic groups in the molecule, the invention also includes, in
addition to the salt forms mentioned, inner salts or betaines.

The respective salts of the compounds according to the
invention can be obtained by customary methods which are known to the person skilled
in the art, for example by contacting these with an organic or inorganic acid or
base in a solvent or dispersant, or by anion exchange or cation exchange with other
salts.

Furthermore, the invention includes all salts of the compounds
according to the invention which, owing to low physiological compatibility, are
not directly suitable for use in pharmaceuticals but which can be used, for example,
as intermediates for chemical reactions or for the preparation of pharmaceutically
acceptable salts or which might be suitable for studying &ggr;-secretase modulating
activity of a compound according of the invention in any suitable manner, such as
any suitable in vitro assay.

The present invention furthermore includes all solvates
of the compounds according to the invention.

The present invention furthermore includes derivatives/prodrugs
(including the salts thereof) of the compounds according to the invention which
contain physiologically tolerable and cleavable groups and which are metabolized
in animals, preferably mammals, most preferably humans into a compound according
to the invention.

The present invention furthermore includes the metabolites
of the compounds according to the invention.

The term "metabolites" refers to all molecules derived
from any of the compounds according to the invention in a cell or organism, preferably
mammal.

Preferably the term "metabolites" relates to molecules
which differ from any molecule which is present in any such cell or organism under
physiological conditions.

The structure of the metabolites of the compounds according
to the invention will be obvious to any person skilled in the art, using the various
appropriate methods.

The compounds according to general formula (I) can be prepared
according to methods published in the literature or by analogous methods.

Depending on the circumstances of the individual case,
in order to avoid side reactions during the synthesis of a compound of the general
formula (I), it can be necessary or advantageous to temporarily block functional
groups by introducing protective groups and to deprotect them in a later stage of
the synthesis, or to introduce functional groups in the form of precursor groups
and at a later stage to convert them into the desired functional groups. Suitable
synthetic strategies, protective groups and precursor groups are known to the person
skilled in the art.

If desired, the compounds of the formula (I) can be purified
by customary purification procedures, for example by recrystallization or chromatography.
The starting materials for the preparation of the compounds of the formula (I) are
commercially available or can be prepared according to or analogously to literature
procedures.

These can serve as a basis for the preparation of the other
compounds according to the invention by several methods well known to the person
skilled in the art.

The invention also relates to a compound of the invention
for use as a medicament. The compounds are as defined above, furthermore with respect
to the medicament the embodiments as desribed below with respect to the use of the
invention, e.g. formulation, application and combination, also apply to this aspect
of the invention.

In particular the compounds according to the invention
are suitable for the treatment of Alzheimer's disease.

Details relating to said use are further disclosed below.

The compounds can be used for modulation of &ggr;-secretase
activity.

As used herein, the term "modulation of &ggr;-secretase
activity" refers to an effect on the processing of APP by the &ggr;-secretase-complex.
Preferably it refers to an effect in which the overall rate of processing of APP
remains essentially as without the application of said compounds, but in which the
relative quantities of the processed products are changed, more preferably in such
a way that the amount of the A&bgr;42-peptide produced is reduced. For example
a different Abeta species can be produced (e.g. Abeta-38 or other Abeta peptide
species of shorter amino acid sequence instead of Abeta-42) or the relative quantities
of the products are different (e.g. the ratio of Abeta-40 to Abeta-42 is changed,
preferably increased).
Gamma secretase activity can e.g. be measured by determining APP processing, e.g.
by determining the levels of Abeta petide species produced, most importantly levels
of Abeta-42 (see Example section, infra).

It has been previously shown that the &ggr;-secretase
complex is also involved in the processing of the Notch-protein. Notch is a signaling
protein which plays a crucial role in developmental processes (e.g. reviewed in
Schweisguth F (2004) Curr. Biol. 14, R129).

With respect to the use of said compounds for the modulation
of &ggr;-secretase activity in therapy, it seems particularly advantageous not
to interfere with the Notch-processing activity of the &ggr;-secretase activity
in order to avoid putative undesired side-effects.
Thus, compounds are preferred which do not show an effect on the Notch-processing
activity of the &ggr;-secretase-complex.

Within the meaning of the invention, "effect on the Notch
processing activity" includes both an inhibition or an activation of the Notch-processing
activity by a certain factor.
A compound is defined as not having an effect on the Notch processing activity,
if said factor is smaller than 20, preferably smaller than 10, more preferably smaller
than 5, most preferably smaller than 2 in the respective assay as described in
Shimizu et al (2000) Mol. Cell. Biol, 20: 6913 at a concentration of 30 µM.
Such a &ggr;-secretase modulation can be carried out, e.g. in animals such as
mammals. Exemplary mammals are mice, rats, guinea pigs, monkeys, dogs, cats. The
modulation can also be carried out in humans. In a particular embodiment of the
invention, said modulation is performed in vitro or in cell culture. As known to
the person skilled in the art, several in vitro and cell culture assays are available.

Exemplary assays useful for measuring the prodction of
C-terminal APP fragments in cell lines or transgenic animals by Western blot analysis
include but are not limited to those described in Yan et al., 1999, Nature 402, 533-537.

An example of an in vitro &ggr;-secretase assay is described
in WO-03/008635. In this assay a suitable peptide substrate is contacted with a &ggr;-secretase
preparation and the ability to cleave the substrate is measured..

Concentrations of the various products of the &ggr;-secretase
cleavage (the Aß-peptides) can be determined by various methods known to a
person skilled in the art. Examples for such methods include determination of the
peptides by mass-spectrometry or detection by antibodies.

Exemplary assays useful for the characterization of the
profile of soluble Abeta peptides in cultured cell media and biological fluids include
but are not limited to those described by Wang et al., 1996, J. Biol. Chem. 271, 31894-31902. In this assay a combination of immunoprecipitation of Abeta-peptides
with specific antibodies and detection and quantification of the peptide species
with matrix-assisted laser desorption ionization time-of-flight mass spectrometry
is used.

Exemplary assays useful for measuring the production of
Abeta-40 and Abeta-42 peptides by ELISA include but are not limited to those described
in Vassar et al, 1999, Science 286, 735-741. Further information is disclosed for example in N. Ida et al. (1996) J. Biol. Chem. 271, 22908, and M. Jensen et al. (2000) Mol. Med. 6, 291. Suitable antibodies are available for example from The Genetics Company,
Inc., Switzerland. Antibody-based kits are also available from Innogenetics, Belgium.

Cells which can be employed in such assays include cells
which endogenously express the &ggr;-secretase complex and transfected cells which
transiently or stably express some or all interactors of the &ggr;-secretase complex.
Numerous available cell lines suitable for such assays are known to the skilled
person. Cells and cell lines of neuronal or glial origin are particularly suitable.
Furthermore, cells and tissues of the brain as well as homogenates and membrane
preparations thereof may be used (Xia et al., 1998, Biochemistry 37, 16465-16471).

Such assays might be carried out for example to study the
effect of the compounds according to the invention in different experimental conditions
and configurations.

Furthermore, such assays might be carried out as part of
functional studies on the &ggr;-secretase complex.
For example, either one or more interactors (either in their wild-type form or carrying
certain mutations and/or modifications) of the &ggr;-secretase complex of an animal,
preferably a mammal, more preferably humans, might be expressed in certain cell
lines and the effect of the compounds according to the invention might be studied.

Mutated forms of the interactor(s) used can either be mutated
forms which have been described in certain animals, preferably mammals, more preferably
humans or mutated forms which have not previously been described in said animals.

Modifications of the interactors of the &ggr;-secretase
complex include both any physiological modification of said interactors and other
modifications which have been described as modifications of proteins in a biological
system.

Examples of such modifications include, but are not limited
to, glycosylation, phosphorylation, prenylation, myristylation and farnesylation.

Furthermore, the compounds according to the invention can
be used for the preparation of a medicament for the modulation of &ggr;-secretase
activity.

The invention further relates to the use of said compounds
for the preparation of a medicament for the modulation of &ggr;-secretase activity.

The activity of the &ggr;-secretase can be modulated
in different ways, i.e. resulting in different profiles of the various A&bgr;-peptides.

Uses of a compound for the modulation of &ggr;-secretase
activity resulting in a decrease in the relative amount of A&bgr;42-peptides produced
are preferred.
Respective dosages, routes of administration, formulations etc are disclosed further
below.

The invention further relates to the use of the compounds
according to the invention for the treatment of a disease associated with an elevated
level of A&bgr;42-production. The disease with elevated levels of Abeta peptide
production and deposition in the brain is typically Alzheimer's disease (AD), cerebral
amyloid angiopathy, multi-infarct dementia, dementia pugilistica or Down syndrome,
preferably AD.

As used herein, the term "treatment" is intended to refer
to all processes, wherein there may be a slowing, interrupting, arresting, or stopping
of the progression of a disease, but does not necessarily indicate a total elimination
of all symptoms.
As used herein, the term "elevated level of A&bgr;42-production" refers to a condition
in which the rate of production of A&bgr;42-peptide is increased due to an overall
increase in the processing of APP or, preferably, it refers to a condition in which
the production of the A&bgr;42 peptide is increased due to a modification of the
APP-processing profile in comparison to the wild-type APP and non-pathological situation.

As outlined above, such an elevated A&bgr;42-level is
a hallmark of patients developing or suffering from Alzheimer's disease.

One advantage of the compounds or a part of the compounds
of the present invention may lie in their enhanced CNS-penetration.

Furthermore the invention relates to a pharmaceutical composition
comprising a compound according to the invention in a mixture with an inert carrier.

In a preferred embodiment, the invention relates to a pharmaceutical
composition comprising a compound according to the invention in a mixture with an
inert carrier, where said inert carrier is a pharmaceutical carrier.

The term "carrier" refers to a diluent, adjuvant, excipient,
or vehicle with which the compound is administered. Such pharmaceutical carriers
can be sterile liquids, such as water and oils, including those of petroleum, animal,
vegetable or synthetic origin, including but not limited to peanut oil, soybean
oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the
pharmaceutical composition is administered orally. Saline and aqueous dextrose are
preferred carriers when the pharmaceutical composition is administered intravenously.
Saline solutions and aqueous dextrose and glycerol solutions are preferably employed
as liquid carriers for injectable solutions. Suitable pharmaceutical excipients
include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica
gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk,
glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired,
can also contain minor amounts of wetting or emulsifying agents, or pH buffering
agents. These compositions can take the form of solutions, suspensions, emulsions,
tablets, pills, capsules, powders, sustained-release formulations and the like.
The composition can be formulated as a suppository, with traditional binders and
carriers such as triglycerides. Oral formulation can include standard carriers such
as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium
saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical
carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.
Such compositions will contain a therapeutically effective amount of the compound,
preferably in purified form, together with a suitable amount of carrier so as to
provide the form for proper administration to the patient. The formulation should
suit the mode of administration.

Furthermore, the invention relates to methods for the preparation
of a compound according to the invention.
In one embodiment for the preparation of a compound according to the present invention,
a dibromofluorobenzene can be treated with a benzyl alcohol in the presence of an
alkali metal hydride, typically sodium hydride, in a suitable aprotic solvent such
as tetrahydrofuran. The product can be treated with a suitable malonic acid derivative,
such as malonic acid tert-butyl ester ethyl ester in the presence of an alkali metal
hydride, typically sodium hydride and a metal halide, typically a copper halide,
preferably copper bromide. Further treatment in an acidic solvent such as acetic
acid at elevated temperature provides a benzyloxy-bromophenylacetic acid ester.
This can be coupled to a boronic acid under the variety of conditions known to those
skilled in the art for such Suzuki coupling, typically using solvents such as 1,2-dimethoxyethane
and water, an alkali metal carbonate such as potassium carbonate, and a palladium
compound such as tetrakis(triphenylphosphine)palladium (0).
If required the compound can be alkylated by treatment in a suitable aprotic solvent
such as tetrahydrofuran with a suitable base such as a metal dialkylamide, typically
LDA, and the appropriate halide at a suitable temperature, typically -78°C
Removal of the benzyl protecting group can be achieved under the variety of conditions
known to those skilled in the art for such deprotections, typically using a palladium
catalyst such as 10% palladium on charcoal in a suitable solvent, such as ethanol,
and under an atmosphere of hydrogen.
The phenol can be converted to a biphenyl ether by a variety of methods known to
those skilled in the art eg DA Evans et al Tetrahedron Lett. (1998), 39, 2937, Hosseinzadeh R et al Synlett (2005), 7, 1101. Typically the phenol is treated with a tertiary amine, such as triethylamine,
a metal acetate, such as copper acetate, an aryl boronic acid and a suitable solvent
such as dichloromethane in the presence of an agent such as 4A molecular sieves.
Conversion of the ester to the acid can be done using a base such as an alkali metal
hydroxide, typically potassium hydroxide in the presence of water and other suitable
solvents such as methanol.
In another embodiment, compounds where A is S can be prepared by the treatment of
a dibromofluorobenzene with an aryl thiol in the presence of a suitable base such
as potassium carbonate, in a suitable aprotic solvent such as N,N,dimethylformamide.
The product can be treated with a suitable malonic acid derivative, such as malonic
acid tert-butyl ester ethyl ester in the presence of an alkali metal hydride, typically
sodium hydride and a metal halide, typically a copper halide, preferably copper
bromide. Further treatment in an acidic solvent such as acetic acid at elevated
temperature provides an arylthio-bromophenylacetic acid ester. This can be coupled
to a boronic acid under the variety of conditions known to those skilled in the
art for such Suzuki coupling, typically using solvents such as 1,2-dimethoxyethane
and water, an alkali metal carbonate such as potassium carbonate, and a palladium
compound such as tetrakis(triphenylphosphine)palladium (0).
If required the compound can be alkylated by treatment in a suitable aprotic solvent
such as tetrahydrofuran with a suitable base such as a metal dialkylamide, typically
LDA, and the appropriate halide at a suitable temperature, typically -78°C
Conversion of the ester to the acid can be done using a base such as an alkali metal
hydroxide, typically potassium hydroxide in the presence of water and other suitable
solvents such as methanol.
In another embodiment for the preparation of a compound according to the present
invention where A is NH, a dibromofluorobenzene can be treated with a benzyl alcohol
in the presence of an alkali metal hydride, typically sodium hydride, in a suitable
aprotic solvent such as tetrahydrofuran. The product can be treated with a suitable
malonic acid derivative, such as malonic acid tert-butyl ester ethyl ester in the
presence of an alkali metal hydride, typically sodium hydride and a metal halide,
typically a copper halide, preferably copper bromide. Further treatment in an acidic
solvent such as acetic acid at elevated temperature provides a benzyloxy-bromophenylacetic
acid ester. This can be coupled to an aniline under the variety of conditions known
to those skilled in the art for such Hartwig-Buchwald coupling, typically such as
described by Hartwig JF in Modern Arene Chemistry, (2002) pp107-168.
Removal of the benzyl ether protecting group can be achieved under the variety of
conditions known to those skilled in the art for such deprotections, typically using
a palladium catalyst such as 10% palladium on charcoal in a suitable solvent, such
as ethanol, and under an atmosphere of hydrogen.
The resultant hydroxycompound can be converted to a triflate using eg trifluoromethanesulphonic
anhydride, an organic base such as pyridine and in a suitable solvent such as dichloromethane.
This triflate can then be coupled to a boronic acid under the variety of conditions
known to those skilled in the art for such Suzuki coupling, typically using solvents
such as 1,2-dimethoxyethane and water, an alkali metal carbonate such as potassium
carbonate, and a palladium compound such as bis(tri-tert-butylphosphine)palladium
(0).
If required the product can be alkylated by treatment in a suitable aprotic solvent
such as tetrahydrofuran with a suitable base such as a metal alkylamide, typically
LDA, and the appropriate halide at a suitable temperature, typically -78°C
Conversion of the ester to the acid can be done using a base such as an alkali metal
hydroxide, typically sodium hydroxide in the presence of water and other suitable
solvents such as ethanol.

When compounds of the invention are produced as racemates,
these can be separated into their enantiomers by methods known to those skilled
in the art, typically by using a chiral HPLC column.

Furthermore, the invention relates to a method for the
preparation of a medicament comprising the steps of:

a) preparing a compound according to the invention

b) formulation of a medicament containing said compound.

The compounds according to the invention and their pharmaceutically
acceptable salts, optionally in combination with other pharmaceutically active compounds
are suitable to treat or prevent Alzheimer's disease or the symptons thereof. Such
additional compounds include cognition-enhancing drugs such as acetylcholinesterase
inhibitors (e.g. Donepezil, Tacrine, Galantamine, Rivastigmin), NMDA antagonists
(e.g. Memantine) PDE4 inhibitors (e.g. Ariflo) or any other drug known to a person
skilled in the art suitable to treat or prevent Alzheimer's disease. Such compounds
also include cholesterol-lowering drugs such as statins (e.g. simvastatin). These
compounds can be administered to animals, preferably to mammals, and in particular
humans, as pharmaceuticals by themselves, in mixtures with one anther or in the
form of pharmaceutical preparations.

Various delivery systems are known and can be used to administer
a compound of the invention for the treatment of Alzheimer's disease or for the
modulation of the &ggr;-secretase activity, e.g. encapsulation in liposomes, microparticles,
and microcapsules:

If not delivered directly to the central nervous system, preferably the brain,
it is advantageous to select and/or modify methods of administration in such a way
as to allow the pharmaceutical compound to cross the blood-brain barrier.

The compounds may be administered by any convenient route,
for example by infusion, by bolus injection, by absorption through epithelial or
mucocutaneous linings and may be administered together with other biologically active
agents.

Administration can be systemic or local. In addition, it
may be desirable to introduce the pharmaceutical compositions of the invention into
the central nervous system by any suitable route, including intraventricular and
intrathecal injection; intraventricular injection may be facilitated by an intraventricular
catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary
administration can also be employed, e.g. by use of an inhaler or nebulizer, and
formulation with an aerosolizing agent.

In another embodiment, the compound can be delivered in
a vesicle, in particular a liposome (Langer (1990) Science 249, 1527.

In order to select an appropriate way of administration,
the person skilled in the art will also consider routes of administration which
have been selected for other known Anti-Alzheimer-drugs.

For example, Aricept/Donepezil and Cognex/Tacrine (all
acetylcholinesterase-inhibitors) are being taken orally, Axura/Memantine (an NMDA-receptor
antagonist) has been launched both as tablets/liquid and as an i.v.-solution.

Furthermore, the skilled person in the art will take into
account the available data with respect to routes of administration of members of
the NSAID-family in clinical trials and other studies investigating their effect
on Alzheimer's disease.

In order to select the appropriate dosage, the person skilled
in the art will choose a dosage which has been shown to be not toxic in preclinical
and/or clinical studies and which can be in accordance with the values given beforehand,
or which may deviate from these.

The precise dose to be employed in the formulation will
also depend on the route of administration, and the seriousness of the disease or
disorder, and should be decided according to the judgment of the practitioner and
each patient's circumstances. However, suitable dosage ranges for intravenous administration
are generally about 20-500 micrograms of active compound per kilogram body weight.
Suitable dosage ranges for intranasal administration are generally about 0.01 mg/kg
body weight to 1 mg/kg body weight. Effective doses may be extrapolated from dose-response
curves derived from in vitro or animal model test systems.

All reactions were carried out under inert atmosphere unless
otherwise stated. NMR spectra were obtained on a Bruker dpx400. LCMS was carried
out on an Agilent 1100 using a ZORBAX® SB-C18, 4.6 x 75 mm, 3.5
micron column for method A. Column flow was 1m1/min and solvents used were water
and acetonitrile (0.1%TFA) with an injection volume of 10u1. Wavelengths were 254
and 210nm. Methods are described below:

2-(5-Benzyloxy-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic
acid ethyl ester (1.1g, 2.4mmol) was dissolved in EtOH (10 mL) and stirred with
10% Pd/C (116 mg) under an atmosphere of hydrogen. After 19h, the mixture was filtered
through Celite and concentrated in vacuo to afford 2-(5-hydroxy-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic
acid ethyl ester (0.85 g) as a colourless oil.

The ester was dissolved in THF (1.2 mL) and treated with
a 1M solution of KOH in 6:1 MeOH/water (0.3 mL, 2 eq). After 65 h, the mixture was
diluted with water (5 mL) then acidified with 1M HCl(aq). The mixture was extracted
with ethyl acetate (2 x 5 mL), then the combined organic layer was washed with brine;
dried (MgSO4) and concentrated in vacuo to afford 2-(5-(4-fluorophenoxy)-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic
acid (57 mg, 90%) as a pale yellow gum. LCMS Method A - 3.65 min.

In an analogous fashion to Example 1 using phenylboronic
acid in place of 4-fluorophenylboronic acid was prepared 2-(5-(phenoxy)-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic
acid LCMS Method A- 3.69 min.

Example 3: Determination of the effect of the compounds according to the invention
on cyclooxygenase-1 and cyclooxygenase -2 (Cox-1, Cox-2)

A&bgr;42 lowering agents of the invention can be used
to treat AD in mammals such as humans or alternatively in a validated animal model
such as the mouse, rat, or guinea pig. The mammal may not be diagnosed with AD,
or may not have a genetic predisposition for AD, but may be transgenic such that
it overproduces and eventually deposits A&bgr; in a manner similar to that seen
in humans afflicted with AD..

A&bgr;42 lowering agents can be administered in any standard
form using any standard method. For example, but not limited to, A&bgr;42 lowering
agents can be in the form of liquid, tablets or capsules that are taken orally or
by injection. A&bgr;42 lowering agents can be administered at any dose that is
sufficient to significantly reduce levels of A&bgr;42 in the blood, blood plasma,
serum, cerebrospinal fluid (CSF), or brain.

To determine whether acute administration of an A&bgr;42
lowering agent would reduce A&bgr;42 levels in vivo, two to three month old Tg2576
mice expressing APP695 containing the "Swedish" variant can be used or alternatively
a transgenic mouse model developed by Dr. Fred Van Leuven (K.U.Leuven, Belgium)
and co-workers, with neuron-specific expression of a clinical mutant of the human
amyloid precursor protein [V717I] (Moechars et al., 1999 J. Biol. Chem. 274, 6483). The single transgenic mouse displays spontaneous, progressive accumulation
of &bgr;-amyloid (A&bgr;) in the brain, eventually resulting in amyloid plaques
within subiculum, hippocampus and cortex. Animals of this age have high levels of
A&bgr; in the brain but no detectable A&bgr; deposition. Mice treated with the
A&bgr;42 lowering agent will be examined and compared to those untreated or treated
with vehicle and brain levels of soluble A&bgr;42 and total A&bgr; would be
quantitated by standard techniques, for example, using ELISA. Treatment periods
may vary from hours to days and will be adjusted based on the results of the A&bgr;42
lowering once a time course of onset of effect can be established.

A typical protocol for measuring A&bgr;42 lowering in
vivo is shown but it is only one of many variations that could be used to optimize
the levels of detectable A&bgr;. For example, aliquots of compounds can be dissolved
in DMSO (volume equal to 1/10th of the final formulation volume), vortexed and further
diluted (1:10) with a 10 % (w/v) hydroxypropyl &bgr; cyclodextrin (HBC, Aldrich,
Ref N° 33,260-7) solution in PBS, where after they are sonicated for 20 seconds.

A&bgr;42 lowering agents may be administered as a single
oral dose given three to four hours before sacrifice and analysis or alternatively
could be given over a course of days and the animals sacrificed three to four hours
after the final dose is given.

Blood is collected at sacrifice. The blood collection is
performed via a heart puncture during anesthesia with a mixture of Ketalar (Ketamin),
Rompun (Xylazin 2%) and Atropin (2:1:1) and collected in EDTA treated collection
tubes. Blood is centrifuged at 4000 g for 5 minutes at 4°C and the plasma recovered
for analysis.

The mice are anaesthetized with a mixture of Ketalar (Ketamin),
Rompun (Xylazin 2%) and Atropin (2:1:1) and flushed trans-cardially with physiological
serum at 4°C.

The brain is removed from the cranium and hindbrain and
forebrain are separated with a cut in the coronal/frontal plane. The cerebellum
is removed. The forebrain is divided evenly into left and right hemisphere by using
a midline sagital cut.

One hemisphere is immediately immersed in liquid nitrogen
and stored at -70°C until homogenization for biochemical assays.

Samples are transferred from -70°C into a sample holder
with liquid nitrogen and each individual sample is pre-warmed by incubation on the
bench for a few seconds prior to homogenization. The homogenates are collected in
Beckman centrifuge tubes TLX and collected on ice prior to centrifugation. Between
two samples, the Potter and the glass tube are rinsed carefully with distilled water
without detergents and dried with absorption paper.

Small reversed phase columns (C18-Sep-Pack Vac 3cc cartridges,
Waters, Massachusetts, MA) are mounted on a vacuum system and washed with 80% acetonitrile
in 0, 1 % Trifluoroacetic acid (A-TFA) followed with 0, 1 % TFA twice. Then the
samples are applied and the columns are washed successively with 5% and 25% A-TFA.
Amyloid peptides are eluted with 75% A-TFA and the eluates are collected in 2 ml
tubes on ice. Eluates are freeze-dried in a speedvac concentrator (Savant, Farmingdale,
NY) overnight and resolved in 240 µl of the sample diluent furnished with the
ELISA kits.

To quantify the amount of human A&bgr;-42 in the soluble
fraction of the brain homogenates, commercially available Enzyme-Linked-Immunosorbent-Assay
(ELISA) kits are used (h Amyloid &bgr;42 ELISA high sensitive, The Genetics Company,
Zurich, Switzerland). The ELISA is performed according to the manufacturer's protocol.
Briefly, the standard (a dilution of synthetic A&bgr;1-42) and samples are prepared
in a 96-well polypropylene plate without protein binding capacity (Greiner bio-one,
Frickenhausen, Germany). The standard dilutions with final concentrations of 1000,
500, 250, 125, 62.5, 31.3 and 15.6 pg/ml and the samples are prepared in the sample
diluent, furnished with the ELISA kit, to a final volume of 60 µl. Samples,
standards and blancs (50 µl) are added to the anti-A&bgr;-coated polystyrol
plate (capture antibody selectively recognizes the C-terminal end of the antigen)
in addition with a selective anti-A&bgr;-antibody conjugate (biotinylated detection
antibody) and incubated overnight at 4°C in order to allow formation of the
antibody-Amyloid-antibody-complex. The following day, a Streptavidine-Peroxidase-Conjugate
is added, followed 30 minutes later by an addition of TMB/peroxide mixture, resulting
in the conversion of the substrate into a colored product. This reaction is stopped
by the addition of sulfuric acid (1M) and the color intensity is measured by means
of photometry with an ELISA-reader with a 450 nm filter. Quantification of the Abeta
content of the samples is obtained by comparing absorbance to a standard curve made
with synthetic A&bgr;1-42.

In such a model at least 20% A&bgr;42 lowering compared
to untreated animals would be advantageous.

Anspruch[en]

A compound having the general formula (I)
wherein
A is O, NH, S;
X is a bond or a group -CR5R6 wherein R5 and R6
are, independently of each other, selected from the group consisting ofH; alkyl
selected from the group CH3, C2H5, i-C3H7,
n-C3H7, i-C4H9, n-C4H9,
sec-C4H9, tert-C4H9; alkenyl selected
from C2H3, i-C3H5, n-C3H5,
n-C4H7, i-C4H7, sec-C4H7;
wherein in the all named alkyl and alkenyl groups one or more H atom is optionally
substituted with one or more substituents independently selected from the group
consisting of F, Cl, Br, I and CF3; or R5 and R6
being part of a ring, either saturated or unsaturated, substituted or unsubstituted,
having 3 to 6 C-atoms, and which may contain in the ring one or more heteroatoms
from the group N, S or O, and which heteroatom may be identical or different if
more than one heteroatom is present;
R1, R2, R3 and R4 are independently
selected from the group consisting of H; F; Cl; Br; I; CN; OH; C(O)N(R7R8);
S(O)2R7; SO2N(R7R8); S(O)N(R7R8);
N(R7)S(O)2R8; N(R8)S(O)R8;
S(O)2R7; N(R7)S(O)2N(R8R8a);
SR7; N(R7R8); N(R7)C(O)R8;
N(R7)C(O)N(R8R8a); N(R7)C(O)OR8;
OC(O)N(R7R8); C(O)R7; substituted and unsubstituted
C1-C4-alkyl and substituted and unsubstituted C1-C4-alkoxy,
and wherein the substituents of both groups C1-C4-alkyl and
C1-C4-alkoxy are selected from F, Cl, Br, I, CF3;
R7, R8, R8a are independently selected from the
group consisting of H; C1-C4-alkyl; heterocyclyl; and C3-7
cycloalkyl, wherein C1-C4-alkyl; heterocyclyl; and C3-7
cycloalkyl are optionally substituted with one or more substituents independently
selected from the group consisting of F, Cl, Br, I and CF3;
Y is a carboxy group -C(O)OH or a substututed or unsubstituted tetrazole group;
and/or a salt or ester thereofThe compound according to claim 1, wherein A; X; Y; R1 and
R2; and R3, R4, independently of each other have
the following meanings:
AisO;X is group -CR5R6 wherein R5 and R6
are, independently of each other, selected from the group consisting of H; alkyl
selected from the group CH3, C2H5, i-C3H7,
n-C3H7, i-C4H9, n-C4H9,
sec-C4H9, tert-C4H9; wherein in the
all named alkyl groups one or more H atom is optionally substituted with one or
more substituents independently selected from the group consisting of F, Cl, Br
and I; and/orR1, R2, R3 and R4 are independently
selected from the group consisting of H; OH; C1-C4-alkyl or
C1-C4-alkoxy, substituted partly or fully by F, Cl, Br, I; and/orY is a carboxy groupand/or a salt or ester thereofThe compound according to claim 1 or 2, wherein A; X; Y; R1
and R2; and R3, R4, R5 and R6
independently of each other have the following meanings:
AisO; X is a group -CR5R6 with R5 and R6
being H; or R5 being H and R6 being CH3,C2H5, C3H7 or C4H9
or isomers thereof; or R5 and R6 being CH3 or R5,
R6 jointly form together with the carbon atom to which they are attached
a cyclopropyl ring;and/orR1, R2, R3 and R4 are independently
selected from the group consisting of H; OH;C1-C4-alkyl or C1-C4-alkoxy, substituted partly
or fully by F, Cl, Br, I; and/orand/orY is a carboxy groupand/or a salt or ester thereofThe compound according to any of claims 1 to 3, wherein A; X; R1
and R2; and R3, R4, R5 and R6
independently of each other have the following meanings:
A is O;X is a X is a group -CR5R6 with R5
and R6 being H; or R5 being H and R6 being CH3,
C2H5, C3H7 or C4H9
or isomers thereof and/orY is a carboxy groupR1, R2, R3 and R4 are independently
selected from the group consisting ofH, OH, CH3, OCH3, CF3,
F, and Cl; and/orand/or a salt or ester thereof.A compound according to claim 1 selected from the group consisting of
2-(5-(4-fluorophenoxy)-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid (I)
2-(5-(phenoxy)-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid (II)
and/or a salt or ester thereof. A compound according to any of claims 1 to 5 for use as a medicament.Use of a compound according to any of claims 1 to 5 for the preparation
of a medicament for the modulation of &ggr;-secretase.Use of a compound according to any of claims 1 to 5 for the preparation
of a medicament for the treatment of a disease associated with an elevated level
of A&bgr;42-production.Use of a compound according to any of claims 1 to 5 for the preparation
of a medicament for the treatment of Alzheimer's disease.A pharmaceutical composition comprising a compound according to any
of claims 1 to 5 in admixture with an inert carrier.A process for the preparation of a compound according to any of claims
1 to 5 with A being O, comprising the following steps:
- treating a dihalidefluorobenzene compound, preferably dibromofluorobenzene,
with a benzyl alcohol in the presence of an alkali metal hydride;- treating the product with a suitable malonic ester derivative in the
presence of an alkali metal hydride and a metal halide;- treatment in an acidic solvent; - coupling to a boronic acid derivative;- removal of the benzyl ether protecting group;- converting the resulting hydroxycompound to a triflate and coupling
to a boronic acid;- optionally alkylating the resulting compound;- removal of the benzyl protecting group;- converting the phenol to a biphenyl ether;- conversion of the ester to the acid.A process for the preparation of a compound according to any of claims
1 to 5 with A being S, comprising the steps as laid out in claim 11, with the exception
that the alkali metal hydride is replaced by a suitable base and the benzyl alcohol
is replaced by an aryl thiol.A process for the preparation of a compound according to any of claims
1 to 5 with A being NH, comprising the following steps:
- treating a dihalidefluorobenzene compound, preferably dibromofluorobenzene,
with a benzyl alcohol in the presence of an alkali metal hydride;- treating the product with a suitable malonic ester derivative in the
presence of an alkali metal hydride and a metal halide;- treatment in an acidic solvent;- coupling to an aniline- removal of the benzyl ether protecting group;- converting the resulting hydroxycompound to a triflate and coupling
to a boronic acid;- optionally alkylating the resulting product;- conversion of the ester to the acid.Method for the preparation of a medicament comprising the steps of:
a) preparing a compound according to any of claims 1 to 5; andb) formulation of a medicament containing said compound.A method of treating a mammal for the modulation of &ggr;-secretase,
which method comprises administering to said mammal a compound according to any
of claims 1 to 5.A method of treating in a mammal a disease associated with an elevated
level of A&bgr;42-production, which method comprises administering to said mammal
a compound according to any of claims 1 to 5.A method of treating Alzheimer's disease in a mammal, which method comprises
administering to said mammal a compound according to any of claims 1 to 5.